This document discusses dyslipidemia and its relationship to stroke risk. It defines dyslipidemia as abnormal lipid levels that can contribute to atherosclerosis. While dyslipidemia is a risk factor for ischemic stroke, the relationship is complex as lipid levels also influence risks of hemorrhagic stroke. Studies show LDL cholesterol in particular is strongly associated with increased ischemic stroke risk, while low cholesterol may raise risks of hemorrhage. Triglycerides and lipoprotein(a) levels also influence stroke risk. Screening lipid profiles after stroke is recommended to guide treatment and reduce future risks.

1. DYSLIPIDEMIA IN STROKE
Dr. Sunil Kumar Sharma
Senior Resident
Moderator
Dr. Dilip Maheshwari (DM)
Asso. Professor
Dept. of Neurology
GMC Kota

2. DYSLIPIDEMIA
 Dyslipidemia is elevation of plasma cholesterol,
TGs, or both, or a low HDL level that contributes to
the development of atherosclerosis.
 Causes may be primary (genetic) or secondary
(DM, Alcohol overuse, CKD, Hypothyroidism, PBC
and Drugs)
 Diagnosis is by measuring plasma levels of total
cholesterol, HDL, TGs, and individual lipoproteins.

3.  There is no natural cutoff between normal and
abnormal lipid levels .
 A linear relation probably exists between lipid levels
and cardiovascular risk, so many people with
“normal” cholesterol levels benefit from achieving
still lower levels.
 There are no numeric definitions of dyslipidemia;
the term is applied to lipid levels for which treatment
has proven beneficial.
MERCK MANUAL ; Professional / Endocrine and Metabolic Disorders / Lipid Disorders Dyslipidemia (Hyperlipidemia) By Anne Carol
Goldberg, MD, Washington University School of Medicine

4. Jacobson et al NLA Dyslipidemia Recommendations - Part 1Journal of Clinical Lipidology (2015) 9, 129–169

5.  Proof of benefit is strongest for lowering elevated
low-density lipoprotein (LDL) levels.
 Less strong evidence of benefit from lowering
elevated TG and increasing low HDL levels.
 The main indication for dyslipidemia treatment is
prevention of atherosclerotic cardiovascular
disease (ASCVD), that include acute coronary
syndromes, stroke, transient ischemic attack, or
peripheral arterial disease .
MERCK MANUAL ; Professional / Endocrine and Metabolic Disorders / Lipid Disorders Dyslipidemia (Hyperlipidemia) By Anne Carol
Goldberg, MD, Washington University School of Medicine

6. LIPID PARAMETERS AND STROKE RISK
 In most epidemiological cohorts, there is a direct
relationship between cholesterol levels and
ischemic stroke.
 Associations is strongest for atherosclerotic
subtypes.
 Increased risk of ICH and small vessel disease at
low cholesterol levels.

7. LIPID PARAMETERS AND STROKE RISK…
 The relationship between dyslipidemia and
cerebrovascular disease (CVD), including stroke is
complex.
 Because of the heterogeneity of CVD and competing
risks from other age related diseases associated with
lipid levels.
 Overall there is strong evidence that lowering LDL-C
reduces the risk of ischemic stroke, with a modest
increase in risk of intracerebral hemorrhage.
Oxford Medicine Online Chapter: Dyslipidemia and Risk of Stroke and Cerebrovascular Disease Author(s): Sabrina Schilling, Christophe
Tzourio, and Stéphanie Debette DOI: 10.1093/med/9780199895847.003.0013; Published online: Apr 2016

8. LIPID PARAMETERS AND STROKE RISK…
 LDL cholesterol has a stronger correlation than
TC and HDL-C.
 LDL cholesterol initiates inflammation and
forms plaques in blood vessel wall, which
inhibits blood flow in arteries.
 Controlling the LDL-C level in patients with
acute ischemic stroke at admission can
improve their prognosis
Adibhatla RM and Hatcher JF. Lipid oxidation and peroxidation in CNS health and disease: from molecular mechanisms to therapeutic
opportunities. Antioxid Redox Signal, 2010; 12, 125-69.

9.  Higher levels of HDL cholesterol were associated
with a significant decrease in risk of nonfatal stroke.
 In contrast, elevated total cholesterol showed a
weak positive association with nonfatal strokes.
 Some studies observed an inverse relationship
between serum TC (or LDL-C) and hemorrhagic
stroke, mainly intracerebral hemorrhage.
Okamura T, Kadowaki T, Hayakawa T, Kita Y, Okayama A, Ueshima H: Nippon Data80 Research Group: What cause of mortality can we
predict by cholesterol screening in the Japanese general population? J Intern Med 2003; 253: 169–180.
Noda H, Iso H, Irie F, Sairenchi T, Ohtaka E, Doi M, Izumi Y, Ohta H: Low-density lipoprotein cholesterol concentrations and death due to
intraparenchymal hemorrhage: the Ibaraki Prefectural Health Study. Circulation 2009; 119: 2136–2145.

10.  Hypotheses to explain the inverse association
between cholesterol and intracerebral hemorrhage.
1- Low blood cholesterol may induce angionecrosis,
possibly in association with hypertension.
2- Low blood cholesterol may reflect poor nutritional
status, which is known to be related to death after
onset of stroke, but not to onset per se.
3-There may be some residual confounding factors.
Okamura T: Low blood cholesterol and intraparenchymal hemorrhage in cohort studies. J Atheroscler Thromb 2010; 17: 312–314.

11. HDL–C AND STROKE
 HDL cholesterol is inversely associated with risk of
nonfatal stroke (presumably ischemic) in both
smokers and non smokers and , men with
preexisting CHD and was particularly striking in
hypertensive men.
 In hypertensives, elevated HDL -C was associated
with a 50% reduction in the risk of nonfatal strokes.
 Caution should be taken in using b-blockers in
hypertensive men because these drugs tend to
lower HDL cholesterol by up to 10% and to raise
triglycerides by up to 30%.
Evans K, Laker MF. Intra-individual factors affecting lipid, lipoprotein and apolipoprotein measurement: a review. Ann Clin Biochem.
1995;32:261–280.

12. HDL–C AND STROKE…
 HDL has 2 main subfractions: larger and less dense
HDL-C (HDL2) and smaller and denser HDL-C
(HDL3).
 These subfractions differ in their biological activity,
biochemical properties, and vascular metabolism.
 HDL3, more so than HDL2, seems to inhibit LDL
oxidation and protect against atherosclerosis by its
action on the vascular endothelium.

13. HDL–C AND STROKE…
 In the Northern Manhattan Study (NOMAS), HDL
subfractions had differential effects on the risk of
carotid disease.
 Direct relationship between HDL2 and plaque
thickness
 Inverse relationship between HDL3 and plaque
area.
Tiozzo E, Gardener H, Hudson BI, Dong C, DellaMorte D, Crisby M, et al. Highdensitylipoprotein subfractions and carotid plaque: The northern
manhattan study. Atherosclerosis. 2014;237:163–168.

14. TRIGLYCERIDES AND STROKE
 Epidemiological studies evaluating triglycerides and
ischemic stroke also show mixed results.
 In a meta-analysis of 64 studies, there was an
association between higher triglyceride levels and
relative risk of stroke for each 10-mg/dL increase in
baseline triglycerides.
 Studies have also shown that triglycerides levels
are inversely associated with hemorrhagic stroke
risk.
Labreuche J, Deplanque D, Touboul PJ, Bruckert E, Amarenco P. Association between change in plasma triglyceride levels and risk of stroke and
carotid atherosclerosis: Systematic review and metaregression analysis. Atherosclerosis. 2010;212:9–15. [

15. LIPOPROTEIN (A) AND STROKE
 An emerging risk factor for cardiovascular disease.
 Plasma levels of Lp(a) are influenced by genetic
factors, with substantial differences across ethnic
groups, with levels being highest among blacks.
 In Atherosclerosis Risk in Communities, Lp(a)
levels ≥30 mg/mL – a/w increased risk of ischemic
stroke in black and white women, but not in white
men.
Gurdasani D, Sjouke B, Tsimikas S, Hovingh GK, Luben RN, Wainwright NW, et al. Lipoprotein(a) and risk of coronary, cerebrovascular, and
peripheral artery disease: The epicnorfolk prospective population study. Arteriosclerosis, thrombosis, and vascular biology. 2012;32:3058–

16. LIPOPROTEIN (A) AND STROKE…
 In a NOMAS case–control study, Lp(a) levels ≥30
mg/dL at baseline were associated with an
increased risk of ischemic stroke.
 This association was more pronounced among men
and blacks.
 The effects of Lp(a), therefore, may depend on
race-ethnic and other demographic factors.

17. IMP. STUDIES
 Assn. of dyslipidemia –CAD is well established .
 The effect of hypercholesterolemia on cerebral
infarction remains controversial, even in Western
populations.
 A positive association between TC and cerebral
infarction was observed in the multiple risk factor
intervention trial (MRFIT) in the U.S. and in the
Copenhagen City Heart Study in Europe.
cholesterol levels and six-year mortality from stroke in 350,977 men screened for the multiple risk factor intervention trial. N Engl J Med 1989; 320:
904–910.
Lindenstrøm E, Boysen G, Nyboe J: Influence of total cholesterol, high-density lipoprotein cholesterol, and triglycerides on risk of cerebrovascular

20. ARIC study-
 TC was not associated with increased risk of total
cerebral infarction, although hypercholesterolemia
was associated with non-lacunar, non-embolic
stroke (i.e., atherothrombotic stroke).
 Similar results were observed in the Hisayama
study. A very large meta-analysis of individual data
from 61 prospective studies, most of which were
carried out in U.S. and European populations,
showed no independent positive association
between TC and ischemic and total stroke mortality.
Plasma Lipid Profile and Incident Ischemic Stroke The Atherosclerosis Risk in Communities (ARIC) Study;Eyal Shahar, MD, MPH; Lloyd E.
Chambless, PhD; Wayne D. Rosamond, PhD; Lori L. Boland, MPH;Christie M. Ballantyne, MD; Paul G. McGovern, PhD†; A. Richey Sharrett, MD, DrPH
I DOI: 10.1161/01.STR.0000057812.51734.FF
mamura T, Doi Y, Arima H, Yonemoto K, Hata J, Kubo M, Tanizaki Y, Ibayashi S, Iida M, Kiyohara Y: LDL cholesterol and the development of stroke
subtypes and coronary heart disease in ageneral Japanese population: the Hisayama study. Stroke 2009; 40: 382–388

23.  The majority of cohort studies in Japan failed to
demonstrate a positive relationship between
hypercholesterolemia and stroke

26. SCREENING FOR LIPID LEVELS AFTER
STROKE
 A serum lipid profile including TC, LDL, HDL, and
triglycerides should be performed.
 Routine testing for other lipid components such as
Lp(a) and HDL subfractions is not recommended.
 The timing of lipid measurements after stroke may
be less important than after myocardial infarction
(MI)
Kargman DE, Tuck C, Berglund L, Lin IF, Mukherjee RS, Thompson EV, et al. Lipid and lipoprotein levels remain stable in acute ischemic stroke:
The northern manhattan stroke study. Atherosclerosis. 1998;139:391–399.

27.  There is evidence that lipid levels after stroke do
not decline as markedly as after MI.
 In a metaanalysis of 68 studies that included over
300,000 patients-the association between lipid
components and ischemic stroke persisted even
when measured in non fasting patients.
Di Angelantonio E, Sarwar N, Perry P, Kaptoge S, Ray KK, Thompson A, et al. Major lipids, apolipoproteins, and risk of vascular disease. Jama.
2009;302:1993–2000.

28.  Associations with triglycerides were even more
prominent in the nonfasting state.
 Therefore, while the lipid profile is preferably
measured fasting, it can probably be tested even in
the nonfasting state, and at any time after the
stroke.
Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, et al. 2013 acc/aha guideline on the treatment of blood cholesterol to
reduce atherosclerotic cardiovascular risk in adults: A report of the american college of cardiology/american heart association task force on practice
guidelines. J Am Coll Cardiol. 2014;63:2889–2934.

29. LIPID-LOWERING THERAPY AND STROKE
 Statins have demonstrated efficacy in reducing
stroke risk.
 In primary stroke prevention trials- 11% to 40%.
 The Heart Protection Study (HPS-2002) -
randomized >20 000 patients aged 40 to 80 years
with high risk of vascular disease to simvastatin 40
mg daily versus placebo.
 There was a 25% reduction in stroke risk without an
increase in the risk of hemorrhagic stroke.

30.  In the Treating to New Targets (TNT)
study(2004)- compared with Atorvastatin 10 mg
daily, Atorvastatin 80 mg daily was associated with
a 25% reduction in stroke risk that correlated with
reductions in LDL.

31.  The Stroke Prevention by Aggressive Reduction
in Cholesterol Levels (SPARCL) trial-
 SPARCL randomized 4731 patients with stroke or
transient ischemic attack and baseline LDL 100 to
190 mg/dL to atorvastatin 80 mg versus placebo
beginning 1 to 6 months after their event.
 After almost 5 years of follow-up
 16% reduction in the risk of stroke compared with
patients on placebo.
 A small increase in hemorrhagic stroke was
reported in the Atorvastatin group.
SPARCL: the glimmer of statins for stroke risk reduction. PubMed NCBI PMID: 18001616

32. The Long- Term Intervention with Pravastatin in
Ischaemic Disease (LIPID) study-
 investigated cholesterol lowering with Pravastatin in
patients with a previous myocardial infarction (MI) or
unstable angina who had cholesterol levels between
155 and 271 mg/dL
 A remarkable reduction in MI, cardiac
revascularizations, and cardiovascular deaths, as
well as a 20% reduction in the risk for stroke
(Long-Term Intervention with Pravastatin in Ischaemic Disease [LIPID] Study Group, 1998).

33.  The Anglo-Scandinavian Cardiac Outcomes
Trial (ASCOT)- randomized 19 342 hypertensive
persons who also had ≥3 other cardiovascular risk
factors to treatment
 A β-blocker ± diuretic or
 CCB (Amlo.)± ACE inhibitor(Perindopril) with follow-
up for 5 years.

34.  Reduced the risk of strokes by about 25%,
 Coronary events and procedures by 15%,
 Cardiovascular deaths by 25%,
 New cases of diabetes by 30% compared with
standard treatment of atenolol plus a diuretic.
 The addition of atorvastatin still further reduced the
remaining risk, irrespective of the patient's original
cholesterol level,

35.  In the Myocardial Ischemia Reduction with
Aggressive Cholesterol Lowering (MIRACL) trial
conducted in patients with unstable angina or non–
Q-wave MI immediately after the qualifying event,
there was a significant overall risk reduction in the
secondary end point of stroke (51%; P=0.04).
 Thus, statins may reduce thromboembolism to the
brain by preventing early recurrent MI.

36.  The benefits of Pravastatin treatment in elderly was
observed in the PROSPER trial.
 It was seen that Pravastatin lowered LDL
concentrations by 34% and the risk of CAD and non
fatal MI was also reduced.
 PROSPER therefore extends the treatment strategy
to elderly as used for middle aged population.

37.  All patients with ischemic stroke, regardless of
subtype, should receive statin therapy.
 There are other potential mechanisms by which
statins are protective
1. Inhibition of the inflammatory cascade,
2. Antioxidant effects,
3. Upregulation of nitric oxide synthase with
consequent increase in cerebral blood flow,
4. Plaque stabilization,
5. Modulating coagulation and platelet function.

38.  Benefit of statins is independent of baseline
cholesterol.
 Statins affect multiple biological systems, including
the immune system.
 Prevention of vascular outcomes in trials of statins
is strongly linked to a decrease in C-reactive
protein.

39.  Statins produce significant reductions in carotid
intimal-medial thickness and decrease aortic
atherosclerosis, a known source of cerebral
embolization.
 Lipid abnormalities may also play a role in small-
vessel disease.

40. EARLY STATIN THERAPY IN PATIENTS WITH ACUTE
INTRACEREBRAL HEMORRHAGE WITHOUT PRIOR
STATIN USE-2013
 Patients taking statins during hospitalization or within 3
months post-discharge were the early statin group (n =
749); patients who were not were the control group (n
= 7583).
 The study end-points were recurrent ICH and all-cause
mortality during follow-up
 Early statin group patients with acute ICH did not have a
higher recurrent risk of ICH and might have lower all-
cause mortality during follow-up.
 It is concluded that statin therapy might be beneficial for
patients with ICH.
Early statin therapy in patients with acute intracerebral hemorrhage without prior statin use;P.-S. Chen et al;DOI: 10.1111/ene.12649

41. NON-STATIN LIPID-LOWERING AGENTS
 Not well established.
 Although niacin increases HDL levels, its benefit in
reducing the risk of cerebrovascular events remains
uncertain.
 Fibric acid derivatives can also be used to lower
triglycerides and increase HDL-C levels, but their
efficacy in reducing incident stroke is uncertain.
 Ezetimibe inhibits the intestinal absorption of
cholesterol, reducing TC levels.

42.  Proprotein convertase subtilisin-kexin type 9
(PCSK9) is a hepatic protease that degrades
hepatic LDL receptors leading to increased serum
LDL-C levels.
 Monoclonal antibody inhibitors of PCSK9
(Alirocumab 75–150 mg sc q 2 wk, Evolocumab
140 mg sc q 2 wk) are novel parenterally(SC)
administered lipid-lowering - reduce LDL by 60% to
70% when added to statin therapy.

43. COMBINATION DRUG THERAPY
 Combination therapy may be considered for
patients who have not reached their treatment
goals for atherogenic cholesterol levels, particularly
in patients with very high or high risk.
 The maximum tolerated statin dosage should
generally be used before add-on therapy is
considered
 The Improved Reduction of Outcomes: Vytorin
Efficacy International Trial (IMPROVE-IT)-
showed that the addition of ezetimibe 10 mg daily
to simvastatin 40 mg daily resulted in a significant
reduction in stroke risk.
Gudzune KA, Monroe AK, Sharma R, Ranasinghe PD, Chelladurai Y, Robinson KA. Effectiveness of combination therapy with statin and another lipid-
modifying agent compared with intensified statin monotherapy. A systematic review. Ann Intern Med. 2014; 160:468–476.

44. COMBINATION DRUG THERAPY…
 Several nonstatins also have RCT evidence for
ASCVD reduction as statin adjuncts in subgroup
analyses of patients with elevated triglycerides or
elevated triglycerides plus low HDL-C
concentrations.
 These include eicosapentaenoic acid ethyl esters,
fibrates and niacin.
Maki K, Bays H, Dicklin M. Treatment options for the management of hypertriglyceridemia: strategies based on the best-available evidence.
J Clin Lipidol. 2012;6:413–426.
Yokoyama M, Origasa H, Matsuzaki M, et al, Japan EPA lipid intervention study (JELIS) Investigators. Effects of eicosapentaenoic acid on major
coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet. 2007; 369:1090–1098
Erratum in Lancet. 2007;370:220.
ACCORD Study Group, Ginsberg HN, Elam MB, Lovato LC, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med.
2010;362:1563–1574 Erratum in N Engl J Med. 2010;362:1748

47. Dyslipidemia Endocrine and Metabolic Disorders Merck Manuals Professional Edition

50. ASCVD RISK HAS BEEN CLASSIFIED INTO 4
CATEGORIES-
 Very high–risk conditions
 High risk conditions
 moderate risk conditions
 low risk conditions

52. AHA/ASA GUIDELINES ON PREVENTION OF
RECURRENT STROKE-2011

53. CONCLUSION
 There is a direct relationship between cholesterol
levels and ischemic stroke, and particularly
atherosclerotic disease, and the associations are
strongest for TC and LDL.
 There is an increased risk of ICH at low cholesterol
levels.
 Statins reduce the risk of recurrent stroke after
ischemic stroke.
 Low intensity Rx is given when High/moderate
intensity Rx. not tolerated

54. Thank You

55. REFERRENCES
 Blood Cholesterol Level and Risk of Stroke in Community-
based or Worksite Cohort Studies: A Review of Japanese
Cohort Studies in the Past 20 years;Taichiro Tanaka1 and
Tomonori Okamura2; (Accepted for publication on November
17, 2011).
 HDL-Cholesterol, Total Cholesterol, and the Risk of Stroke in
Middle-Aged British Men;S. Goya Wannamethee, PhD; A.
Gerald Shaper, FRCP; S. Ebrahim, FRCP; May 5, 2000.
 National Lipid Association Recommendations for Patient-
Centered Management of Dyslipidemia: Part 1—Full Report
Terry A. Jacobson, MD et al; Journal of Clinical Lipidology
(2015) 9, 129–169 http://dx.doi.org/10.1016/j.jacl.2015.02.003

56.  Lipids and Cerebrovascular Disease. Shadi Yaghi, et al. Stroke
November 2015.
 Lipid Profile Components and Subclinical Cerebrovascular
Disease in the Northern Manhattan Study. Joshua Z. Willey, et al.
Cerebrovasc Dis 2014;37:423–430.
 Lipid profile in cerebrovascular accidents. T Mansoureh, et al. Ir J
neurol 2011; 10(1-2): 1-4.
 Statin treatment withdrawal in ischemic stroke A controlled
randomized study. M. Blanco, et al.
 The Role of Statins in Vascular Disease. P. E. Laws, et al. Eur J
Vasc Endovasc Surg 27, 6–16 (2004).